Summary
The pharmacology, toxicology and kinetics of a new diuretic indapamide, have been studied in six normal volunteers following a single oral dose of 40 mg. Pronounced diuresis was found, commencing three hours after ingestion, with a peak urinary flow at four to six hours, and continuing for a total of thirty-six hours. A fall in systolic standing blood pressure occurred twenty four hours after ingestion, coincident with the period of maximum dehydration. Free water clearance rose, accompanied by increased urinary losses of Na+, K+ and Cl− and alkalinisation of the urine comparable to the actions of benzothiadiazines. Total urinary losses of Ca2+, Mg2+ and PO 3−4 rose in spite of a fall in urinary concentrations of these ions. The Ca2+ effect compares with the acute ionic effects of other diuretics. No renal, hepatic or haematological toxic effect was demonstrated. The blood sugar level was not disturbed. Serum uric acid rose to abnormal levels although the change did not reach statistical significance. — A thin layer chromatographic method, with a sensitivity limit of 0.1 µg/ml., has been developed for the assay of indapamide in urine. The urinary excretion rates of the volunteers measured over forty-eight hours indicate that the drug is rapidly absorbed with a peak excretion, 2.9±1.3 µg/min occurring three hours after ingestion. The drug is eliminated bi-phasically with an initial short rapid elimination followed by a slower exponential decline with a mean elimination half-life of 10.3 ± 3.9 h. The mean urinary excretion of unchanged indapamide over forty-eight hours was 4.4±1.4% of the administered dose. — It is concluded that indapamide is an effective long-acting diuretic with comparable action to the benzothiadiazine diuretics, but without an effect on blood sugar level in single doses in normal subjects. In contrast with other diuretics, indapamide appears to be extensively metabolised in man, and its longer duration of action to be related to a longer elimination half-life.
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Beyer, K.H., Baer, J.E., Michaelson, J.K., Russo, H.F.: Renotropic characteristics of ethacrynic acid: A phenoxyacetic saluretic diuretic agent. J. Pharmacol. exp. Ther.147, 1–22 (1965)
Bratton, A.C., Marshall, E.K., Jr.: A new coupling component for sulfanilamide determinations. J. biol. Chem.128, 537–550 (1939)
Breckenridge, A.M.: Hypertension and hyperuricaemia. Lancet1966 I, 15–18
Breckenridge, A., Dollery, C.T., Welborn, T.A., Fraser, R.: Glucose tolerance in hypertensive patients on long-term diuretic therapy. Lancet1967 I, 61–64
Brettel, H.R., Aikama, J.K., Gordon, G.A.: Studies with chlorothiazide tagged with radioactive carbon (C14) in human beings. Arch. intern. Med.106, 109–115 (1960)
Brickman, A.S., Massry, S.G., Coburn, J.W.: Changes in serum and urinary calcium during treatment with hydrochlorothiazide: studies on mechanisms. J. clin. Invest.51, 945–954 (1972)
Callingham, B.A.: Current aspects of pharmacology: diuretics. Pharm. J.207, 60–62 (1971)
Cornish, A.L., McClellan, J.T., Johnston, D.H.: Effects of chlorothiazide on the pancreas. New Engl. J. Med.265, 673–675 (1961)
Demartini, F.E. Briscoe, A.M., Ragan, C.: Effect of ethacrynic acid on calcium and magnesium excretion. Proc. Soc. exp. Biol. (N.Y.)124, 320–324 (1967)
Duarte, C.G., Winnacker, J.L., Becker, K.L.: Thiazide induced hypercalcaemia. New Engl. J. Med.284, 828–830 (1971)
Feisal, K.A., Eckstein, J.W., Horsley, A.W., Keasling, H.H.: Effects of chlorothiazide on forearm vascular responses to norepinephrine. J. appl. Physiol.16, 549–552 (1961)
Fries, E.D., Wanko, A., Schnaper, H.W., Frohlich, E.D.: Mechanism of the altered blood pressure responsiveness produced by chlorothiazide. J. clin. Invest.39, 1277–1281 (1960)
Grayson, M.F., Smith, A.J., Smith, R.N.: Absorption, distribution and elimination of C14-amiloride in normal human subjects. Brit. J. Pharmacol.43, 473 (1971)
Haussler, A., Hajdu, P.: Untersuchungen mit dem Salidiureticum 4-Chlor-N-(furylmethyl)-5-sulfamyl-anthramil-Säure. Arzneimittel-Forsch.14, 713–716 (1964)
Healey, L.A., Magid, G.J., Decker, J.L.: Uric acid retention due to hydrochlorothiazide. New Engl. J. Med.261, 1358–1362 (1959)
Imbs, J.L., Schwarz, J.: Personal communication (1972)
Johnston, D.H., Cornish, A.L.: Acute pancreatitis in patients receiving chlorothiazide. J. Amer. med. Ass.170, 2054–2056 (1959)
Kohner, E.M., Lowy, C., Dollery, C.T., Schumer, B.: Effect of diuretic therapy on glucose tolerance in hypertensive patients. Lancet1971 I, 986–990
Koppel, M.H., Shinaberger, J.H., Massry, S.G., Popovtzer, M., Coburn, J.W.: Hypercalcaemic response to hydrochlorothiazide in uraemia: Evidence for an extrarenal effect on calcium metabolism. Ann. intern. Med.72, 803 (1970)
Laubie, M.: Etude pharmacologique d'un nouveau diurétique (S. 1520) de longue durée d'action (in preparation). Personal communication (1972)
Marignan, R., Chanal, L., Blanchard, M.S.: Personal communication (1972)
McCurdo, R.: Thrombocytopenic purpura due to chlorothiazide. Practitioner192, 403 (1964)
McQueen, E.G., Morrison, R.B.I.: The hypotensive action of diuretic agents. Lancet1960 I, 1209–1212
Merrill, J.P., Guinand-Baldo, A., Giordano, C.: The effect of chlorothiazide on norepinephrine response in human hypertension. Clin. Res.6, 230 (1958)
Paloyan, E., Forland, M., Pickleman, J.R.: Hyperparathyroidism coexisting with hypertension and prolonged thiazide administration. J. Amer. med. Ass.210, 1243–1245 (1969)
Parfitt, A.M.: Chlorothiazide-induced hypercalcaemia in juvenile osteoporosis and hyperparathyroidism. New Engl. J. Med. 281, 55–59 (1969)
Saaman, N.A., Dollery, C.T., Fraser, R.: Diabetogenic action of benzothiadiazines. Lancet1963 I, 1244–1246
Schotland, M.G., Grumbach, M.M.: Neutropenia in an infant secondary to hydrochlorothiazide therapy. With a review of haematological reactions to ‘thiazide’ drugs. Pediatrics31, 754–757 (1963)
Sheppard, H., Moroles, T.F., Bowen, N., Renzi, A.A., Plummer, A.J.: Distribution and fate of hydrochlorothiazide-3H. Toxicol. appl. Pharmacol.2, 188–194 (1960)
Smith, L.H.: Hazards of thiazide treatment of renal lithiasis. J. Amer. med. Ass.208, 540 (1969)
Suki, W.N., Hull, A.R., Rector, F.C., Seldin, D.W.: Mechanism of the effect of thiazide diuretics on calcium and uric acid. Clin. Res.15, 78 (1967)
Suki, W.N., Yium, J.J., von Minden, M., Saller-Hebert, C., Eknoyan, G., Martinez-Maldonado, M.: Acute treatment of hypercalcaemia with furosemide. New Engl. J. Med.283, 836–840 (1970)
Wagner, J.G.: Use of computers in pharmacokinetics. Clin. Pharmacol. Ther.8, 201–218 (1967)
Weiss, P., Hersey, R.M., Dujorne, C.A., Bianchine, J.R.: The metabolism of amiloride hydrochloride in man. Clin. Pharmacol. Ther.10, 401–406 (1969)
Weller, J.M., Borondy, M.: Inhibitory effect of chlorothiazidein vitro on glucose metabolism of adipose tissue. Proc. Soc. exp. Biol. (N.Y.)124, 220–223 (1967)
Wenger, J., Gross, P.R.: Acute pancreatitis related to hydrochlorothiazide therapy. Gastroenterology46, 768 (1964)
Yendt, E.R., Gagne, R.J.A., Cohanim, M.: The effects of thiazides in idiopathic hypercalciuria. Amer. J. med. Sciences251, 449–460 (1966)
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Campbell, D.B., Phillips, E.M. Short term effects and urinary excretion of the new diuretic, indapamide, in normal subjects. Eur J Clin Pharmacol 7, 407–414 (1974). https://doi.org/10.1007/BF00560352
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DOI: https://doi.org/10.1007/BF00560352